Abstract

BackgroundAcromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool. MethodsGHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT). ResultsOf the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to <1ng/ml) and were classified as in remission. 2 of these patients developed recurrent symptoms of acromegaly during follow-up with increasing levels of IGF-1 and sKlotho, and both patients were carriers of the d3-GHR genotype. ConclusionsAcromegalic patients with the d3-GHR polymorphism might be – for a given low postsurgical GH level – at higher risk for recurrence and may require a lower GH nadir during oGTT to be classified as in remission. Soluble Klotho could be useful in the follow-up of acromegalic patients. The question arises whether sKlotho not only reflects the activity of GH-secreting pituitary adenomas but whether Klotho (ectodomain clipping?) could also mediate selected actions of GH.

Highlights

  • As Klotho levels may relate to FGF23 and insulin resistance in acromegaly, it is of particular interest in these patients, and we measured soluble Klotho (sKlotho) in sera of patients before and after transsphenoidal surgery

  • Consistent with the finding that the d3-growth hormone receptor (GHR) shows enhanced growth hormone (GH) signal transduction, acromegalic patients carrying d3-GHR allele, on average, appear to require only half the amount of GH to cause the same increase in insulin like growth factor 1 (IGF-1) and to have a given severity of the disease when they present for diagnosis as do carriers of the full-length isoform (fl-GHR) isoform (Schmid et al, 2007)

  • In particular the 3 patients with increasing IGF-1 levels despite initial postoperative GH suppression

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Summary

Background

Is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. Klotho protein exists in a soluble form which can arise either from a distinct transcript or from secretase-catalyzed ectodomain shedding of membrane Klotho (Imura et al, 2004; Matsumura et al, 1998) It is released into the extracellular space and soluble Klotho (sKlotho) can reach and affect a number of target tissues and processes, including regulation of hormone and growth factor (e.g. inhibition of insulin/IGF-1) signalling, and of ion channel and transporter plasma membrane abundance and activity, e.g. to attenuate calciuria. As Klotho levels may relate to FGF23 and insulin resistance (or high phosphate and glucose, respectively) in acromegaly, it is of particular interest in these patients, and we measured sKlotho in sera of patients before and after transsphenoidal surgery

Effect of the d3-GHR in healthy subjects
Effect of the d3-GHR in a pediatric population with growth deficiency
Effect of the d3-GHR on clinical and biochemical parameters in acromegaly
Relevance of the d3-GHR during follow-up of patients with acromegaly
Relevance of sKlotho during follow-up
Patient examples from the Zurich cohort
Findings
Conclusion
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